Substituted aromatic compounds such as aromatic amines, aromatic ethers, aromatic aldoximes and aromatic aldehydes are useful as biologically active substances (pharmaceuticals, agricultural chemicals), functional materials (liquid crystal materials, electronic materials, optical materials, photographic additives, resins, dyes and the like) or intermediates for the synthesis thereof.
There is generally known, as a method for producing a substituted aromatic compound, a method in which an aromatic compound is metalized with lithium, sodium, magnesium or the like to obtain an arylmetal compound, and then the arylmetal compound is reacted with an electrophilic compound. Also, metalization of a halogenated unsaturated aliphatic compound is similarly known.
Among metals used for metalization of such aromatic compounds and halogenated unsaturated aliphatic compounds, lithium is applied for the synthesis of various compounds from the viewpoint of a wide range of the applicable aromatic compounds and halogenated unsaturated aliphatic compounds, high reactivity and the like.
For example, Patent Document 1 discloses a method for producing an organic charge transporting polymer, which includes the step of lithiating a dihalide of N-(substituted)phenylcarbazole with an alkyl lithium and then reacting with boron trihalide.
Patent Document 2 discloses a producing method in which 4-substituted-2,6-difluorobenzene having an acetal group is lithiated with an alkyl lithium and then reacted with carbon dioxide to obtain a benzoic acid derivative and acid amide, which are then dehydrated.
It is also known that coordinating compounds such as tetramethylethylenediamine, tetramethylpropylenediamine and pentamethyldiethylenetriamine or the like are used so as to activate an organolithium reagent and an organolithium compound. These coordinating compounds may be sometimes chelate-coordinated with an organolithium compound thereby releasing the association state, thus improving the reactivity of the organolithium compound (see, for example, Non-Patent Document 1). However, the addition of these coordinating compounds improves the reactivity of a lithiated compound to be generated, while it causes severe deterioration of the stability. For example, Non-Patent Document 2 discloses that, although a lithiated compound is generated from 1,4-difluorobenzene and n-butyl lithium, the addition of tetramethylethylenediamine causes severe deterioration of the stability of a lithiated compound when compared with the case of no addition.
In metalization by lithium and subsequent introduction of an electrophile, the reaction has been carried out under very low temperature conditions (for example, −60° C. or lower and the like) so as to suppress the reactivity of a highly active organolithium compound (see, for example, Non-Patent Document 3 and Non-Patent Document 5), because it is considered that the yield of an organolithium compound or a substituted aromatic compound is considerably decreased when metalization by lithium is carried out under mild temperature conditions (for example, −20° C. to room temperature). In fact, in metalization by lithium under mild temperature conditions in the presence of tetramethylethylenediamine, the product showed low stability and a low yield (see Comparative Example 2 shown below).
Furthermore, since a reaction of an organolithium compound with an electrophilic compound is accompanied by heat generation, there was a large problem that a special facility such as a liquid nitrogen bubbling device for cooling so as to achieve a high yield of a substituted aromatic compound is required, resulting in high production cost (see, for example, Non-Patent Document 4). Moreover, in the production at industrial scale, there exist burdens in safety measures, for example, limitation on the use amount of organolithium compound, difficulty in control of an exothermic reaction and the like (paragraphs [0011] and [0012] of Patent Document 3).
As described above, in the metalization of an organic compound by lithium and the production of a substituted aromatic compound by introduction of an electrophile into an organolithium compound, there existed the need of the execution of the reaction under very low temperature conditions, and burdens in production costs and safety measures.
Recently, intense interest has been shown towards a method in which metalization by lithium is carried out using a tubular flow type reactor such as a microreactor.
For example, Patent Document 3 describes a production method in which an arylmetal compound is produced in a continuous flow type reactor in the case of producing an arylmetal compound by deprotonation of an aromatic compound having a hydrogen atom at the ortho-position to a halogen atom or a trifluoromethoxy group, or a halogen-metal exchange of a haloaromatic compound using a metalizing reagent, and reacting an arylmetal compound with an electrophilic reagent. However, this method has such a drawback that cooling costs considerably increase since the synthesis of an arylmetal compound in a continuous flow type reactor and the reaction of an arylmetal compound with an electrophilic reagent must be carried out at very low temperature of about −70° C. to −35° C.
Patent Document 4 describes a method for producing a compound useful for drugs, agricultural chemicals, liquid crystals, electrophotographies, dyes and the like, in which a halogen compound is reacted with a lithium reagent for very short residence time to obtain an organolithium compound having an aromatic ring, and then the organolithium compound is reacted with an electrophilic compound immediately before the organolithium compound causes a side reaction such as decomposition.
Patent Document 5 describes a method for producing an o-substituted aromatic compound in which lithiation and electrophilic substitution are carried out by a microreactor. This production method discloses that a chelating agent such as tertiary amine can be added so as to activate an organolithium reagent and an organolithium compound.
These methods provide the possibility of carrying out the synthesis of an organolithium compound which becomes unstable unless the synthesis is carried out under very low temperature conditions and the reaction of the organolithium compound with an electrophile under mild temperature conditions of 0° C. or higher in some cases. However, these methods require a special mixer such as a micromixer. It is also required to precisely control the residence time in a microtube within a very short time of 0.001 to 5 seconds, and a high-performance liquid feeding device is required because of a large pressure loss of a microreactor.
Also, an enormous number of microreactors are required so as to produce a large amount of the objective product because of the very small volume per one reactor usable in the production, and thus high facility costs are required. Furthermore, countermeasures against the phenomenon such as occlusion of a tube and a reactor may become necessary.
As described above, in the continuous flow type reactor (including a microreactor), the operational burden and the burden of safety measures, such as precise control of the residence time and occlusion of the tube tend to increase, which may become large obstacles of commercialization.
[Patent Document 1]
    Japanese Unexamined Application, First Publication No. 2007-262151[Patent Document 2]    Japanese Unexamined Application, First Publication No. 2003-286279[Patent Document 3]    Japanese Unexamined Application, First Publication No. 2000-229981[Patent Document 4]    Japanese Unexamined Application, First Publication No. 2006-241065[Patent Document 5]    Japanese Unexamined Application, First Publication No. 2008-195639[Non-Patent Document 1]    Edited by Ryoji Noyori et al., “Lecture of Graduated School: Organic Chemistry I, Molecular Structure and Reaction/Organometallic Chemistry”, page 320[Non-Patent Document 2]    Scott, J. P.; Berwer, S. E.; Davies, A. J.; Brands, K. M. J. “Preparation, thermal stability and carbonyl addition reactions of 2,5-difluorophenyl lithium and 2,5-difluorophenyl grignard” Synlett 2004, 1646[Non-Patent Document 3]    Zbinden, K. G.; Banner, D. W.; Hilpert, K.; Himber, J.; Lave, T.; Riederer, M. A.; Stahl, M.; Tschopp, T. B.; Obst-Sander, U.; Bioorganic & Medicinal Chemistry 2006, 14, 5357[Non-Patent Document 4]    “Process Development and Pilot Plant Synthesis of Methyl 2-Bromo-6-chlorobenzoate” Organic Process Research & Development 2005, 9, 764-767[Non-Patent Document 5]    LerouX, F.; Hutschenreuter, T. U.; Charriere, C.; Scopelliti, R.; Hartmann, R. W. Helvetica Chimica Acta 2003, 86, 2671.